Orphan Drug Global Incentives & Regulatory Framework

1. Orphan Drug Global Incentives & Regulatory Framework Marlene E. Haffner, MD, MPH CEO, Haffner Associates, LLC Orphan Drugs Summit 2012 Thursday, 27th September 2012

3. Current Pharma Trends • Slow pharma industry growth • Patent expiration • Generic Competition • Drying Pipelines • Biosimilars • Regulatory Guidelines • Lack of Investor Interest • Reduction in ROI • Lack of Success • Economic Uncertainty • Orphan Products Save the Day!?

4. Orphan Drug Development ChallengesThe rarity paradigm • Limited public awareness (invisible patient population) • Scarcity of clinical expertise and reference centers – disease is poorly understood; no natural history • Delay in diagnosis • Small patient population – difficulty in recruiting to clinical trials • Geographic dispersion • Life threatening/chronic • Heterogeneous conditions • Difficult to stratify/stage – lack of natural history of disease • Limited treatment availability

6. Entering Orphan Drug Market • Public Health • Economies of Scale Source: Thomson Reuters Newport Premium, IMS Health

7. Who has Orphan Drug Policies • US – the first 1982/3 • Singapore – 1991 • Japan – 1993 • Australia – 1998 • EU – 1999/2000 • Taiwan, S. Korea, Hong Kong, S. Africa, Turkey, India…

8. Orphan Medical Product Designation

9. US Orphan Drug Policy • Orphan Drug Act (1983) • Rare disease = prevalence < 200,000 • 7 Year Market Exclusivity • FDA Filing Fee Wavier • Tax Credits for clinical trials • Orphan Product Grants • 400+ drugs approved; >2200 designated • Use of accelerated approval/fast track

10. EU Orphan Drug Policy • Orphan Drug Regulation 141/2000 (1999) • Rare disease = prevalence < 5 per 10,000 • 10 Year Market Exclusivity (6 + 4 years) • Must be Serious or Life threatening disease • Free Protocol Assistance; partial waiver filing fee • Tax credits by member state • Grants via 8th Framework • COMP designates – 38 members • chair, 1 from each MS, 3 patient organization members, 3 from CHMP, 1 each Norway, Lichtenstein, Iceland, 1 from EC • 864 designated; 68 approved orphan drugs

11. Japan’s Orphan Drug Policy • Orphan Drug Regulation • Pharmaceutical Affairs Law Amendment (1993) • Rare disease = prevalence < 50,000 (Population 120 million) • 10 Year exclusivity • Various Tax Incentives • 50% reimbursement of development cost • Designation must be for incurable disease with no alternative treatment • Marketing authorization via fast track

12. Japan Source:MHLW Orphan Product Designation System

13. Other Nations Source: Sharma, Abraham, Manas, & Dushyant. "Orphan Drug: Development Trends and Strategies." 

14. Global Cooperation • Improving – orphan diseases do not know territorial boundaries • Approval Process – can have joint US/EU review and approval. Is cumbersome • OOPD and COMP – regular meetings • Designation application – US/EU – same format • Not always aligned on definition of “what is the disease” • Obvious differences in population requirements – surrogate for profitability • EMA and MHLW/PMDA (Pharmaceuticals and Medical Device Agency)

15. Relative contribution of Top-15 countries to the total scientific output for the 88 rare metabolic disorders† 1996-1998 2009-2011 OUT IN † De Vrueh, Remco. "China Has Joined the Fight against Rare Disorders."

16. Latest Orphan Drug Development • Glybera – first Gene therapy. Recommended for approval by CHMP. Awaiting EC approval • Gevokizumab • Multikinaseinhibitor lenvatinibmesylate – thyroid CA – approved in Japan. US/EU studies ongoing • Hemophilia B – AMT – also gene therapy. Not yet approved

17. Working with the regulatory agencies • Approval requirements same for orphan products as for non orphan products. • Product must be safe and effective for its intended use • Not always easy to demonstrate • Frequent post-marketing commitments • Most frequent products are: Metabolic/endocrine; inborn errors; oncology; neurology • 80% genetic • 90 % Serious and/or life threatening (US); 100% serious/life threatening (EU) • 50% children

18. Working with the regulatory agencies • Difficulty in designing adequate clinical trials for such small populations – need excellent statisticians • EU has white paper • FDA will have guidance • May have a preponderance of patients in a member state/nation • Founder effect • Cultural norms

19. Working with the regulatory agencies • Protocol assistance/pre-IND meetings – used in US and EU and Japan. No charge • FDA – Office of Orphan Products Reviews designation and Review Division grants product approval. Consult with each other. Office of Rare Diseases in CDER – works with orphan product policy in CDER • EU – COMP reviews designation with concurrence by EC. Approval by CHMP with concurrence by EC • Concordance between EU and US probably >90% • Differences with disease definition • And population numbers • Designation consultation with MHLW Japan - frequent

20. New US Legislation - 2012 • PDUFA 5/FDASIA – Section IX • To implement more effective processes for expedited development and review of innovative new drugs to meet unmet needs§ 901 (a) • Expands Fast track – “serious and life threatening disease or condition” • Accelerated approval - expands clinical benefit beyond usual surrogate endpoints to include epidemiological, pathophysiological, therapeutic, pharmacologic or other evidence developed using biomarkers

21. New US Legislation • Do the new provisions make a difference? • Allows FDA to do what it has been doing already • Helpful for Orphan Products • Helpful for new FDA reviewers • FDA may also withdraw products more easily

22. Moving Forward • Big PhRMA increasing involvement in Orphan Product Development • Asian Markets - emerging • Gene therapy – on the horizon • Improvements in Diagnosis/Treatment/genetic markers • Need for more Natural History Data • Issues of Access/Cost - especially in individual Member States • New platforms • Chronic therapy – long lived products • Over all - exciting, new technology, serving unmet needs for millions world wide!

23. Marlene E. Haffner, MD, MPH President & CEO 11616 Danville Drive Rockville, Maryland 20852 mhaffner3@verizon.net 301 984 5729 - office 301 641 4268 - cell 301 984 2272 - FAX